Search Results (2,562)

Bovine viral diarrhea (BVD) is a highly infectious disease with a global distribution caused by the bovine viral diarrhea virus (BVDV), primarily affecting cattle. Dairy farms play a central role in the persistence and spread of BVDV in Italy, making control strategies and genetic studies essential to reduce its circulation. This work aimed to identify and characterize the genotype and subgenotype of BVDV infecting cattle in a specific area of Sardinia. Ten BVDV Sardinian strains were isolated and sequenced from the blood of infected cattle collected into EDTA tubes during outbreaks between 2018 and 2024. Then, to characterize the isolates, phylogenetic and variant analyses were performed on the entire collection of BVDV genomes available to date in GenBank. All Sardinian isolates were assigned to the BVDV-1b subgenotype. Except for two divergent strains, the isolates clustered into a distinct monophyletic clade characterized by 61 exclusive variants absent in all other analyzed sequences. These findings point to the existence of a distinct Sardinian genomic signature. Moreover, among these mutations, 19 missenses distributed on genes encoding the E1, E2, Core, NS3, NS4B and NS5A proteins could have a relevant functional impact, given the role these proteins play in the virus life cycle and in interaction with the host. Full article

Hepatocellular carcinoma (HCC) and pancreatic ductal adenocarcinoma (PDAC) are highly lethal cancers marked by profound epigenetic and metabolic reprogramming. Among the candidate biomarkers, the DNA methyltransferase DNMT3A and the guanine monophosphate synthetase (GMPS) have emerged as potential prognostic drivers, yet their roles across tumor contexts remain unclear. Here, we demonstrate the application of KMplotter to interrogated pan-cancer transcriptomic and survival datasets encompassing over 7000 patients, complemented by expression profiling of normal, tumor, and metastatic tissues, and integrated tumor microenvironment (TME) analyses. Elevated DNMT3A and GMPS expression correlated with worse overall survival in HCC, particularly in Asian patients, while in PDAC, high DNMT3A but low GMPS expression predicted favorable outcomes. Both genes were consistently upregulated in tumors relative to normal tissues, with further increases in metastatic HCC. Immune deconvolution revealed that DNMT3A was linked to Th2/Treg-enriched niches, whereas GMPS overexpression coincided with high mutational burden or stromal enrichment, fostering immunosuppressive microenvironments. Comparative analysis of toll-like receptor signatures highlighted divergent antigen-sensing pathways, with HCC reflecting viral-driven immune exhaustion and PDAC showing self-antigen–associated signaling. Collectively, these findings position DNMT3A and GMPS as context-dependent biomarkers that integrate metabolic and immune cues to shape prognosis in liver and pancreatic cancer, offering mechanistic insight and translational relevance for patient stratification. Full article

Background/Objectives: Colorectal cancer (CRC) is the second leading cause of cancer-related death in the US. The presence of deficient DNA mismatch repair and microsatellite instability (dMMR/MSI) in CRC is linked to responses to immune checkpoint inhibitors (ICIs). This study investigates the impact of metformin on the tumor microenvironment (TME) and clinical outcomes of patients with dMMR/MSI CRC treated with ICIs, aiming to better understand its potential role in enhancing ICI efficacy. Methods: Of 25,011 CRC patients in Caris database, 47 received both metformin and ICI therapy (Met-ICI group), and 475 patients received ICI therapy alone (ICI group). Samples underwent genomic or transcriptome sequencing at Caris Life Sciences. Immune cell fractions were estimated using quanTIseq. Univariate and multivariate survival analyses were conducted using the Cox proportional model. Results: The TME analysis of CRC patient samples revealed that TMB-High (≥10 mut/Mb) was more prevalent in the “ICI” group compared to the “Met-ICI” group (99.1% vs. 95.6%, p = 0.036). Mutation rates for most genes between the two groups were similar, but CIC gene mutations were more common in the “ICI” group than in the “Met-ICI” group (23.2% vs. 4.8%, p = 0.006). No significant differences were observed in the PD-L1 positivity rate or immune checkpoint gene expression (including IDO1, IFNG, TIM3, and CTLA4). M1 macrophages and neutrophils showed the highest infiltration among immune cells. However, the fractions of infiltrated immune cells were similar between the two cohorts. Univariate and multivariate analyses showed that there was no significant difference in patient survival between “ICI” and “Met-ICI” cohorts. Conclusions: In this retrospective analysis of real-world clinical outcomes, the concurrent use of metformin with ICIs in patients with dMMR/MSI CRC did not reveal an impact on clinical outcomes. Full article

Background: Biliary tract cancer (BTC) is an aggressive malignancy with poor prognosis and limited therapeutic options. Poly(ADP-ribose) polymerase (PARP) inhibitors have demonstrated efficacy in tumors with homologous recombination repair (HRR) deficiency. However, actionable BRCA1/2 mutations are rare in BTC. Epigenetic modulation via DNA methyltransferase (DNMT) inhibition is a proposed strategy for inducing an HR-deficient (“BRCAness”) phenotype and thereby enhancing therapeutic response to PARP inhibitors. This study aimed to determine whether the DNMT inhibitor azacitidine (AZA) enhances the antitumor effects of the PARP inhibitor niraparib (NIR) and to identify molecular mechanisms underlying this interaction. Methods: Two BTC cell lines, TFK-1 and RBE, were treated with AZA and/or NIR or subjected to siRNA-mediated DNMT1, DNMT3A, or DNMT3B knockdown. Functional analyses included homologous recombination (HR) assays, flow cytometric evaluation of cell-cycle distribution and apoptosis, proliferation and survival assays, and IC₅₀ determination. Whole-transcriptome RNA sequencing was performed to identify differentially expressed genes after AZA treatment or DNMT3B knockdown, followed by validation via qPCR and Western blotting. To explore epigenetic regulation, whole-genome bisulfite sequencing was performed on TFK-1 cells following DNMT3B knockdown. Results: AZA treatment decreased HR frequency in a dose-dependent manner and enhanced the sensitivity of BTC cells to NIR, as evidenced by increased apoptosis, suppressed proliferation, and reduced IC₅₀ values. DNMT3B knockdown recapitulated these effects, establishing a causal relationship between DNMT3B suppression and disrupted HR repair. RNA sequencing identified opioid growth factor receptor (OGFR) as a commonly upregulated gene after DNMT3B knockdown. Functional validation showed that OGFR overexpression reduced HR activity, increased apoptosis, and enhanced NIR sensitivity. Contrarily, OGFR knockdown conferred relative resistance. Whole-genome bisulfite sequencing showed no significant CpG methylation changes at the OGFR promoter region, indicating that OGFR induction is mediated through DNMT3B-dependent transcriptional regulation rather than direct promoter demethylation. Conclusions: DNMT3B inhibition sensitizes BTC cells to PARP inhibitors by disrupting HR repair. OGFR was identified as a novel regulator of HR and PARP inhibitor sensitivity, controlled via noncanonical DNMT3B-dependent transcriptional mechanisms that operate independently of CpG methylation. These findings provide new mechanistic insights into the epigenetic control of DNA repair and support the rationale for combining DNMT and PARP inhibitors as a promising therapeutic strategy for BTC beyond genetically HR-deficient cases. Full article

This study aims to investigate the genomic epidemiological characteristics of enteric adenovirus types F40 and F41 circulating in Yantai from August 2022 to August 2023, with a focus on genetic diversity, recombination events, and their potential implications for public health and vaccine development. A total of 1200 stool specimens were collected from patients with suspected viral diarrhea, and 47 human adenovirus F subgroup positive samples in Yantai were analyzed. HAdV-F subgroup nucleic acid detection and whole-genome sequencing were performed to identify virus types and single nucleotide variants (SNVs). Phylogenetic and recombination analyses were conducted, and viral protein structures were predicted using AlphaFold3. HAdV-F40 strains exhibited relative genetic conservation, with mutations primarily localized to the fiber gene. In contrast, HAdV-F41 strains displayed pronounced genetic divergence, with a higher mutation burden in the hexon gene. Recombination analysis revealed clear intra-typic recombination events within HAdV-F41, particularly in the hexon gene region. Structural modeling indicated that although the overall protein architecture remained intact, amino acid changes in key antigenic regions may influence immune evasion. HAdV-F40 and HAdV-F41 strains circulating in Yantai show marked genetic diversity. Notably, HAdV-F41 undergoes significant recombination events that may enhance viral adaptability and immune escape. These findings provide important molecular evidence to inform future surveillance strategies and vaccine antigen design for HAdV-F subgroups. Full article

Responses to palliative radiotherapy (RT) for metastatic lesions vary among patients, and molecular determinants of radiosensitivity remain unclear. This study investigated genomic features associated with local progression-free survival (LPFS) in metastatic breast cancer patients treated with palliative RT. Forty-four patients who underwent next-generation sequencing of 523 cancer-related genes were retrospectively analyzed. The biologically effective dose (BED) was calculated using an α/β ratio of 3 Gy, and local progression was defined as recurrence or progression within the irradiated field. A total of 60 metastatic lesions, predominantly in bone (68.3%), were evaluated. Higher BED (≥88 Gy) was significantly associated with longer LPFS (p = 0.011). Among 320 detected mutations mapped to 141 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and the PI3K–Akt signaling pathway remained an independent predictor in multivariate analysis (p = 0.03). Subgroup analyses demonstrated that patients with Ras, PI3K–Akt, or FoxO pathway mutations derived greater LPFS benefit from high BED, whereas this advantage was confined to wild-type tumors for the PD-L1/PD-1 checkpoint and choline metabolism pathways. These findings suggest that pathway-specific molecular contexts modulate RT response and may inform individualized radiation dose strategies in metastatic breast cancer. Full article

SARS-CoV-2, the virus responsible for COVID-19, disrupts human cellular pathways through complex protein–protein interaction, contributing to disease progression. As the virus has evolved, emerging variants have exhibited differences in transmissibility, immune evasion, and pathogenicity, underscoring the need to investigate their distinct molecular interactions with host proteins. In this study, we constructed a comprehensive SARS–CoV–2–human protein–protein interaction network and analyzed the temporal evolution of pathway perturbations across different variants. We employed computational approaches, including network-based clustering and functional enrichment analysis, using our custom-developed Python (v3.13) pipeline, BioEnrichPy, to identify key host pathways perturbed by each SARS-CoV-2 variant. Our analyses revealed that while the early variants predominantly targeted respiratory and inflammatory pathways, later variants such as Delta and Omicron exerted more extensive systemic effects, notably impacting neurological and cardiovascular systems. Comparative analyses uncovered distinct, variant-specific molecular adaptations, underscoring the dynamic and evolving nature of SARS-CoV-2–host interactions. Furthermore, we identified host proteins and pathways that represent potential therapeutic vulnerabilities, which appear to have co-evolved with viral mutations. Full article

B-cell leukemia/lymphoma protein 3 (Bcl3), a member of the IκB family proteins, regulates the transcriptional activities of the NF-κB family of transcription factors. It is known that aberrant Bcl3 activities induce malignancies of both hematologic and non-hematologic origins. Overexpressed, mutated and/or phosphorylated Bcl3 has been implicated in several cancers due to its altered transcriptional activities. However, the physiological function of Bcl3 in immune homeostasis remained elusive to date. In this study, Bcl3 knockout zebrafish were generated to investigate its role in immune regulation. Bcl3 deficient zebrafish exhibited growth retardation and significantly reduced survival. Histological analyses revealed the absence of Hassall bodies in the thymus and hepatocellular nuclear abnormalities, indicating compromised integrity of the immune organs. Zebrafish with Bcl3 deficiency further showed enhanced immune responses and increased susceptibility to both bacterial and viral infections, resulting in significantly elevated levels of pro-inflammatory cytokines il1b, il6, il8, and tnfa. Treatment with the anti-inflammatory drug dexamethasone (Dex) effectively alleviated inflammation, downregulated pro-inflammatory cytokine expressions and improved survival. Collectively, our findings demonstrate Bcl3 as a key regulator of immune activation in vivo, highlighting its role in maintaining immune homeostasis and promoting organismal survival. Full article

The abstract has been submitted for presentation to the AANS 2026 meeting being held in San Antonio, TX, USA. Introduction: Oligodendrogliomas are an uncommon subset of gliomas that are molecularly defined by 1p/19q codeletion in the setting of an isocitrate dehydrogenase (IDH) 1/2 mutation. Standard-of-care management involves maximal safe resection followed by adjuvant chemoradiation with procarbazine, lomustine, and vincristine (PCV). Although PCV confers a durable survival advantage, treatment-limiting toxicity is common and often necessitates discontinuation. IDH inhibitors such as vorasidenib have demonstrated promising efficacy and more favorable tolerability profiles, but a paucity of comparative data across therapeutic classes limits optimal treatment decision-making. Methods: A systematic search was conducted through to 7 March 2025 in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR). Eligible studies included adult patients (≥18 years) with IDH-mutant, 1p/19q-codeleted oligodendrogliomas treated with PCV chemotherapy or IDH inhibitors and with a minimum follow-up of 12 months. Outcomes of interest included overall survival (OS), progression-free survival (PFS), and grade ≥ 3 adverse events (AEs) that led to treatment discontinuation. Results: Twenty-eight studies met the inclusion criteria, with a total of 406 patients. All 406 patients carried a confirmed diagnosis of oligodendroglioma. For mixed-histology cohorts, only oligodendroglioma-specific data were extracted and analyzed. Among PCV cohorts, median PFS ranged from 24.3 months to 8.4 years and median OS was reported up to 14.7 years in long-term follow-up from RTOG 9402 and EORTC 26951. Grade ≥ 3 AEs resulted in treatment discontinuation in 65–70% of patients, primarily due to hematologic or neurologic events. In comparison, vorasidenib achieved a median PFS of 27.7 months in the phase III INDIGO trial (HR 0.39; 95% CI 0.27–0.56; p < 0.001), with median OS not yet reached at 14.2 months of follow-up. Grade ≥ 3 AEs occurred in 22.8% of patients and led to treatment discontinuation in only 1–3%, primarily due to asymptomatic transaminitis. Early real-world data from expanded-access programs similarly support these tolerability findings. Conclusions: While PCV chemotherapy remains the standard-of-care systemic therapy for oligodendroglioma supported by mature survival data, IDH inhibitors represent a mechanistically targeted alternative with encouraging early-phase outcomes and a significantly improved safety profile. Direct comparison across these regimens is constrained by differences in study design and limited long-term OS data for IDH inhibitors. Prospective head-to-head trials are essential for defining the optimal therapeutic sequence in this evolving treatment landscape. In the interim, we provide a recommend approach for current use. Full article

Background/Objectives: This study aimed to characterize dendritic cell (DC) heterogeneity, immune associations, and prognostic relevance across three TP53-mutated tumor entities—high-grade serous ovarian cancer (HGSOC), triple-negative breast cancer, and endometrial cancer—focusing on plasmacytoid DCs (pDCs) in HGSOC. Methods: RNA-sequencing and clinical data of 603 patients from The Cancer Genome Atlas were analyzed. DC subset abundance was assessed for cDC progenitor, conventional DC type 1 (cDC1), conventional DC type 2 (cDC2), plasmacytoid DC (pDC), and mature DC by marker gene signatures. Differences in DC scores across tumors were analyzed using Kruskal–Wallis. Survival analyses were performed using Kaplan–Meier and Cox regression. Spearman’s correlation was used to determine associations between parameters. Results: HGSOC showed the lowest pDC abundance, yet high pDC scores were independently associated with shorter PFS (HR = 1.55, 95% CI: 1.05–2.27; p = 0.027), representing the only DC-subset-related prognostic signal observed across tumor types. pDCs correlated positively with neutrophils and negatively with monocytes, and pDCs, cDC2s, and cDC progenitors correlated inversely with TMB. No consistent link was found between pDC and TP53 mutation classes. However, tumors harboring specific TP53 mutations within established hotspot regions exhibited significantly lower pDC levels (p = 0.015). Conclusions: Our findings reveal distinct DC infiltration patterns and highlight the immunological vulnerability of TP53-mutated HGSOC. pDCs appear to exert a tumor-promoting, immune-evasive role, suggesting that DC function depends on their programming and tumor context. Selective targeting of DC subsets may offer novel therapeutic opportunities in TP53-mutated, low-TMB cancers. Full article

Background/Objectives: The Ataxin-2 protein (ATXN2) plays an essential role in RNA metabolism and many cellular processes. Dysregulation or mutation of the Ataxin-2 gene (ATXN2) can lead to neurodegenerative diseases such as spinocerebellar ataxia type 2 (SCA2) and amyotrophic lateral sclerosis (ALS). Despite numerous efforts in this field in other animal models, little is known about Atxn2 in zebrafish. In this study, we aim to investigate the potential suitability of zebrafish as a model for Atxn2-related diseases by performing basic analyses on Atxn2. Methods: We performed a bioinformatic protein analysis of Atxn2 from zebrafish and its paralog Atxn2l in relation to human and other vertebrate homologues. Based on a structural analysis of the atxn2 and atxn2l genes, the expression of the predicted transcripts was detected by RT-PCR and the spatiotemporal expression pattern was determined by whole-mount in situ hybridization. Results: We found similarities between the protein sequences of Atxn2 and Atxn2l in zebrafish and their functional domains with those of orthologs in humans and other vertebrates. The predicted transcripts of atxn2 and atxn2l were experimentally verified and their spatiotemporal expression patterns were determined during zebrafish development. Splicing variants were detected for both genes, suggesting a different role for the isoforms in different tissues. Conclusions: These findings provide new insights into the atxn2 and atxn2l genes, suggesting the zebrafish as a suitable animal model for functional studies and research on disease modeling of SCA2 and ALS. Full article

Human growth hormone (GH) exerts its pleiotropic effects by binding to its receptor (GHR), leading to receptor dimerization and activation. We combined structural, evolutionary, and genetic analyses to elucidate the critical determinants of GH-GHR interaction and the impact of disease-causing mutations. Protein contact analysis revealed the specific amino acid residues involved in two distinct binding interfaces between GH and two chains of GHR. ConSurf analysis demonstrated significant sequence conservation in the receptor-binding regions of GH across species, highlighting their functional importance. A comprehensive list of known disease-causing mutations in GH was compiled and mapped to these binding interfaces and conserved regions. Computational site-directed mutagenesis (SDM) analysis predicted the impact of several mutations on protein stability, revealing both stabilizing and destabilizing effects. Sequence comparisons with orthologs from various species further supported the evolutionary conservation of key functional residues. Integrated analysis of contact residues between GH and GHR showed a strong correlation between receptor-binding residues, evolutionary conservation, and the occurrence of disease-associated mutations. These findings underscore the critical role of specific GH residues in mediating high-affinity interactions with its receptor and how mutations in these conserved contact points can disrupt binding affinity and/or protein stability, ultimately leading to growth disorders. This multi-faceted approach provides valuable insights into the molecular mechanisms underlying growth hormone deficiency and related syndromes. Full article

Marinesco–Sjögren syndrome (MSS) is a rare autosomal recessive disorder characterized by cerebellar ataxia, congenital cataracts, developmental delay, hypotonia, and progressive myopathy. Most reported cases are linked to pathogenic variants in SIL1, a gene encoding a co-chaperone essential for protein folding in the endoplasmic reticulum. Here, we present a comprehensive case study of a Turkish pediatric patient diagnosed with MSS, supported by genetic, bioinformatic, and structural modeling analyses. Whole-exome sequencing revealed a homozygous splice-site variant (SIL1 c.453+1G>T), confirmed by Sanger sequencing and segregation analysis. In silico annotation using Genomize, InterVar, Franklin, VarSome, ClinVar, OMIM, and PubMed classified the variant as pathogenic according to ACMG guidelines. Structural modeling by Phyre2 and I-TASSER demonstrated that the variant abolishes the intron 5 donor site, leading to truncation of the wild-type 461-amino-acid protein into a shortened ~189-amino-acid polypeptide. This truncation results in the loss of critical Armadillo (ARM) repeats required for HSPA5 interaction, explaining the observed instability and impaired chaperone function. Clinically, the patient presented with congenital cataracts, ataxia, developmental delay, and progressive muscle weakness, consistent with previously reported MSS cases. Comparison with the literature confirmed that splice-site variants frequently correlate with severe phenotypes, including early-onset ataxia and cataracts. This report highlights the importance of integrating genomic, structural, and clinical data to better understand genotype–phenotype correlations in MSS. Our findings expand the mutational spectrum of SIL1, reinforce the role of splicing defects in disease pathogenesis, and emphasize the necessity of comprehensive molecular diagnostics for rare neurogenetic syndromes. Full article

Acute myeloid leukemia (AML) continues to carry a dismal prognosis in older adults and those with secondary or high-risk disease, where conventional 7 + 3 chemotherapy has long delivered complete remission rates below 40% and median overall survival often under 6 months. CPX-351 (Vyxeos), a liposomal co-encapsulation of cytarabine and daunorubicin at a fixed synergistic 5:1 molar ratio, was designed to overcome the pharmacokinetic mismatch that undermines the traditional regimen. This review critically examines the preclinical rationale and clinical evidence for CPX-351, with particular attention to whether its nanoparticle platform truly represents a breakthrough or merely an incremental refinement of decades-old cytotoxics. Across phase I–III trials and real-world cohorts, CPX-351 consistently outperformed standard 7 + 3 in its approved populations of newly diagnosed therapy-related AML (t-AML) and AML with myelodysplasia-related changes (AML-MRC) in patients aged 60–75 years. In the pivotal phase III study (n = 309), CPX-351 improved median overall survival from 5.95 to 9.56 months (HR 0.69, 95% CI 0.52–0.90; p = 0.005) and raised the complete remission rate from 33.3% to 47.7%, while facilitating allogeneic transplantation in 34% as opposed to 25% of patients. A five-year follow-up sustained the separation in survival curves, and post-hoc analyses of responders showed median overall survival exceeding 25 months with CPX-351 versus approximately 10 months with 7 + 3 (HR 0.49). Real-world series have reported composite remission rates of 53–60%, measurable residual disease negativity in up to 65% of responders, and median overall survival of 12–20 months, depending on transplant utilization. Despite these gains, the absolute survival benefit remains modest, prolonged cytopenias are universal, and outcomes in TP53-mutated or younger adverse-risk patients are still poor, raising legitimate questions about cost-effectiveness and generalizability. Nonetheless, CPX-351 stands as the first clinically validated example of ratiometric nanomedicine in oncology, proving that reformulating established drugs can yield meaningful progress where novel agents have often failed. Full article

Background: Cavariella salicicola (Hemiptera: Aphidinae) is a pest on Salix spp. and various Umbelliferae (Apiaceae) vegetables. However, the taxonomic status and phylogenetic relationship of the genus Cavariella within Aphidinae remain controversial due to the small body size and easily confused external morphology. Methods: The complete mitochondrial genome of C. salicicola collected from Oenanthe javanica was sequenced using the Illumina platform and compared with C. theobaldi. The codon usage bias of two Cavariella aphids was assessed through Enc plot, PR2 plot, and neutrality plot analyses. Furthermore, phylogenetic trees were constructed based on both Maximum Likelihood and Bayesian Inference analysis. Results: The C. salicicola mitochondrial genome comprises 15,720 bp and represents a typical circular DNA molecule with a high AT content of 83.8%. It contains the standard 37 genes, including 2 ribosomal RNAs (rRNAs), 13 protein-coding genes (PCGs), 22 transfer RNAs (tRNAs), and 2 long non-coding regions (control and repeat regions). Varying degrees of codon usage bias were found across different PCGs, and the bias was predominantly influenced by natural selection rather than mutational pressure. The ratio of nonsynonymous to synonymous substitutions (Ka/Ks) indicated that all PCGs in C. salicicola, as well as most other Aphidinae species, are under strong purifying selection. The phylogenetic analysis based on Maximum Likelihood and Bayesian Inference both strongly supported the monophyly of Aphidinae, Macrosiphini, and Aphidini. Crucially, the monophyletic genus Cavariella was resolved as a sister group to all other sampled species within the tribe Macrosiphini. Conclusions: This study provides new molecular data to support the sister relationship of the genus Cavariella to other Macrosiphini aphids. This study will enhance our understanding of phylogenetic relationships within the subfamily Aphidinae. Full article